Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

Abstract

Background Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. Methods We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. Results Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. Conclusions MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. Trial registration This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Efficacy and biomarker analysis of second‐line nab‐paclitaxel plus sintilimab in patients with advanced biliary tract cancer

“…Similarly, high TMB is a widely used immunotherapy predictive biomarker, but the majority of BTC patients show low TMB, with a median value of approximately 3.7 Muts/Mb. 34 In the present trial, there was only one patient with high TMB/MSI‐H status who obtained PR and is still receiving maintenance sintilimab treatment. Recently, several studies have indicated that PD‐L1‐positive expression is associated with improved therapeutic outcomes, but the specific cutoff values of PD‐L1‐positive tumor cells (tumor cell proportion score, TPS) or tumor cells plus tumor‐associated immune cells (combined positive score, CPS) are not clear.…”